Wichor M. Bramer

Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women: A Systematic Review and Meta-analysis

IMPORTANCE In August 2015, the US Food and Drug Administration (FDA) approved flibanserin as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women, despite concern about suboptimal risk-benefit trade-offs. OBJECTIVE To conduct a systematic review and meta-analysis of randomized clinical trials assessing efficacy and safety of flibanserin for the treatment of HSDD in women. DATA SOURCES Medical databases (among others, Embase, Medline, Psycinfo) and trial registries were searched from inception to June 17, 2015. Reference lists of retrieved studies were searched for additional publications. STUDY SELECTION Randomized clinical trials assessing treatment effects of flibanserin in premenopausal and postmenopausal women were eligible. No age, language, or date restrictions were applied. Abstract and full-text selection was done by 2 independent reviewers. DATA EXTRACTION AND SYNTHESIS Data were extracted by one reviewer and checked by a second reviewer. Results were pooled using 2 approaches depending on the blinding risk of bias. MAIN OUTCOMES AND MEASURES Primary efficacy outcomes included number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes included, among others, 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue. RESULTS Five published and 3 unpublished studies including 5914 women were included. Pooled mean differences for SSE change from baseline were 0.49 (95% CI, 0.32-0.67) between 100-mg flibanserin and placebo, 1.63 (95% CI, 0.45-2.82) for eDiary desire, and 0.27 (95% CI, 0.17-0.38) for FSFI desire. The risk ratio for study discontinuation due to AEs was 2.19 (95% CI, 1.50-3.20). The risk ratio for dizziness was 4.00 (95% CI, 2.56-6.27) in flibanserin vs placebo, 3.97 (95% CI, 3.01-5.24) for somnolence, 2.35 (95% CI, 1.85-2.98) for nausea, and 1.64 (95% CI, 1.27-2.13) for fatigue. Womens mean global impression of improvement scores indicated minimal improvement to no change. CONCLUSIONS AND RELEVANCE Treatment with flibanserin, on average, resulted in one-half additional SSE per month while statistically and clinically significantly increasing the risk of dizziness, somnolence, nausea, and fatigue. Overall, the quality of the evidence was graded as very low. Before flibanserin can be recommended in guidelines and clinical practice, future studies should include women from diverse populations, particularly women with comorbidities, medication use, and surgical menopause.

The role of epigenetic modifications in cardiovascular disease: A systematic review

BACKGROUND Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in processes underlying cardiovascular disease (CVD), including atherosclerosis, inflammation, hypertension and diabetes. METHODS Eleven databases were searched for studies investigating the association between epigenetic marks (either global, site-specific or genome-wide methylation of DNA and histone modifications) and CVD. RESULTS Of the 3459 searched references, 31 studies met our inclusion criteria (26 cross-sectional studies and 5 prospective studies). Overall, 12,648 individuals were included, with total of 4037 CVD events. The global DNA methylation assessed at long-interspersed nuclear element (LINE-1) was inversely associated with CVD, independent of established cardiovascular risk factors. Conversely, a higher degree of global DNA methylation measured at Alu repeats or by the LUMA method was associated with the presence of CVD. The studies reported epigenetic regulation of 34 metabolic genes (involved in fetal growth, glucose and lipid metabolism, inflammation, atherosclerosis and oxidative stress) in blood cells to be related with CVD. Among them, 5 loci were validated and methylation at F2RL3 was reported in two large prospective studies to predict cardiovascular disease beyond the traditional risk factors. CONCLUSIONS Current evidence supports an association between genomic DNA methylation and CVD. However, this review highlights important gaps in the existing evidences including lack of large-scale epigenetic investigations, needed to reliably identify genomic loci where DNA methylation is related to risk of CVD.

The comparative recall of Google Scholar versus PubMed in identical searches for biomedical systematic reviews: a review of searches used in systematic reviews

BackgroundThe usefulness of Google Scholar (GS) as a bibliographic database for biomedical systematic review (SR) searching is a subject of current interest and debate in research circles. Recent research has suggested GS might even be used alone in SR searching. This assertion is challenged here by testing whether GS can locate all studies included in 21 previously published SRs. Second, it examines the recall of GS, taking into account the maximum number of items that can be viewed, and tests whether more complete searches created by an information specialist will improve recall compared to the searches used in the 21 published SRs.MethodsThe authors identified 21 biomedical SRs that had used GS and PubMed as information sources and reported their use of identical, reproducible search strategies in both databases. These search strategies were rerun in GS and PubMed, and analyzed as to their coverage and recall. Efforts were made to improve searches that underperformed in each database.ResultsGS’ overall coverage was higher than PubMed (98% versus 91%) and overall recall is higher in GS: 80% of the references included in the 21 SRs were returned by the original searches in GS versus 68% in PubMed. Only 72% of the included references could be used as they were listed among the first 1,000 hits (the maximum number shown). Practical precision (the number of included references retrieved in the first 1,000, divided by 1,000) was on average 1.9%, which is only slightly lower than in other published SRs. Improving searches with the lowest recall resulted in an increase in recall from 48% to 66% in GS and, in PubMed, from 60% to 85%.ConclusionsAlthough its coverage and precision are acceptable, GS, because of its incomplete recall, should not be used as a single source in SR searching. A specialized, curated medical database such as PubMed provides experienced searchers with tools and functionality that help improve recall, and numerous options in order to optimize precision. Searches for SRs should be performed by experienced searchers creating searches that maximize recall for as many databases as deemed necessary by the search expert.

Encounters between medical specialists and patients with medically unexplained physical symptoms; influences of communication on patient outcomes and use of health care: a literature overview.

Medically unexplained physical symptoms (MUPS) burden patients and health services due to large quantities of consultations and medical interventions. The aim of this study is to determine which elements of communication in non-psychiatric specialist MUPS care influence health outcomes. Systematic search in PubMed, PsycINFO and Embase. Data extraction comprising study design, patient characteristics, number of patients, communication strategies, outcome measures and results. Elements of doctor-patient communication were framed according to symptoms, health anxiety, satisfaction, daily functioning and use of health care. Eight included studies. Two studies described the effect of communication on patient outcome in physical symptoms, three studies on health anxiety and patient satisfaction and one study on daily functioning. Two studies contained research on use of health care. Qualitative synthesis of findings was conducted. Communication matters in non-psychiatric MUPS specialist care. Perceiving patients’ expectations correctly enables specialists to influence patients’ cognitions, to reduce patients’ anxiety and improve patients’ satisfaction. Patients report less symptoms and health anxiety when symptoms are properly explained. Positive interaction and feedback reduces use of health care and improves coping. Development of communication skills focused on MUPS patients should be part of postgraduate education for medical specialists.

The effects of lutein on cardiometabolic health across the life course: a systematic review and meta-analysis

BACKGROUND The antioxidant lutein is suggested as being beneficial to cardiometabolic health because of its protective effect against oxidative stress, but evidence has not systematically been evaluated. OBJECTIVE We aimed to evaluate systematically the effects of lutein (intake or concentrations) on cardiometabolic outcomes in different life stages. DESIGN This is a systematic review with meta-analysis of literature published in MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar up to August 2014. Included were trials and cohort, case-control, and cross-sectional studies in which the association between lutein concentrations, dietary intake, or supplements and cardiometabolic outcomes was reported. Two independent investigators reviewed the articles. RESULTS Seventy-one relevant articles were identified that included a total of 387,569 participants. Only 1 article investigated the effects of lutein during pregnancy, and 3 studied lutein in children. Furthermore, 31 longitudinal, 33 cross-sectional, and 3 intervention studies were conducted in adults. Meta-analysis showed a lower risk of coronary heart disease (pooled RR: 0.88; 95% CI: 0.80, 0.98) and stroke (pooled RR: 0.82; 95% CI: 0.72, 0.93) for the highest compared with the lowest tertile of lutein blood concentration or intake. There was no significant association with type 2 diabetes mellitus (pooled RR: 0.97; 95% CI: 0.77, 1.22), but higher lutein was associated with a lower risk of metabolic syndrome (pooled RR: 0.75; 95% CI: 0.60, 0.92) for the highest compared with the lowest tertile. The literature on risk factors for cardiometabolic diseases showed that lutein might be beneficial for atherosclerosis and inflammatory markers, but there were inconsistent associations with blood pressure, adiposity, insulin resistance, and blood lipids. CONCLUSIONS Our findings suggest that higher dietary intake and higher blood concentrations of lutein are generally associated with better cardiometabolic health. However, evidence mainly comes from observational studies in adults, whereas large-scale intervention studies and studies of lutein during pregnancy and childhood are scarce.

Exploring strategies to operationalize cognitive reserve: A systematic review of reviews

Introduction: The cognitive reserve hypothesis suggests that across the lifespan, higher education, regular participation in social or mentally stimulating activities, and complexity of occupation increase an individual’s resistance to dementia. However, there is currently no consensus regarding how to assess or measure cognitive reserve. Method: We performed a systematic review of reviews focused on the concept of cognitive reserve to examine key elements of the definition and highlight limitations. We searched Embase.com, MEDLINE (OvidSP), the Cochrane Library, Web of Science, Scopus, Google Scholar, and PubMed. Results: Five systematic reviews were identified. These incorporated findings from cohort, cross-sectional, and case-control studies, and the outcomes examined included Alzheimer’s disease, vascular dementia, nonspecified dementia, all dementias, and cognitive decline or cognitive impairment. Education, occupation, and leisure or mentally stimulating activities were suggested to supply cognitive reserve and offer a protective effect against the risk of dementia. Premorbid IQ and socioeconomic status have not been investigated as thoroughly and showed inconsistent results. Two of the reviews showed that when combining different indicators in the analyses/definition, including education, occupation, mentally stimulating activities, and premorbid IQ, cognitive reserve had a protective effect against cognitive decline. However, other indicators may also supply the reserve, including dietary habits and genetic indicators, but research is lacking with regard to creating a full cognitive reserve model. Conclusions: This review highlights the lack of consensus regarding a definition of cognitive reserve. Further research is required to clarify how the indicators already identified may provide cognitive reserve and offer a protective effect against dementia. Agreement on the indicators that constitute the cognitive reserve model is needed before testing possible interventions that may increase the reserve supply and improve cognition.

Effects of choline on health across the life course: a systematic review

CONTEXT Choline is a precursor of both betaine and acetylcholine and might, therefore, influence cardiovascular and cognitive outcomes. There has been concern, however, that it may influence blood lipid levels because it is an essential component of very-low-density lipoproteins. OBJECTIVE The aim was to systematically review, using PRISMA guidelines, the literature pertaining to the effects of choline on body composition and on metabolic, cardiovascular, respiratory, and neurological outcomes in different life stages. DATA SOURCES The MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar databases were searched up to July 2014. DATA EXTRACTION Fifty relevant articles were identified. These comprised trials and cohort, case-control, and cross-sectional studies that assessed blood levels of choline, dietary intake of choline, and supplementation with choline in a population free of diseases at baseline. DATA SYNTHESIS There is some observational evidence that choline during pregnancy may be beneficial for the neurological health of the child. In adults, choline may have beneficial effects on cognition, but high-quality (intervention) studies are lacking. Results on the effects of choline on body composition, blood lipids, and cardiovascular health were inconsistent. CONCLUSIONS Evidence to confirm the suggested effects of choline on health in different stages of life is scarce. Potential effects of choline need to be confirmed by intervention studies. Possible harmful effects on cardiometabolic health need careful evaluation.

Levels of ambient air pollution according to mode of transport: a systematic review

BACKGROUND Controversy exists about the differences in air pollution exposure and inhalation dose between mode of transport. We aimed to review air pollution exposure and inhaled dose according to mode of transport and pollutant and their effect in terms of years of life expectancy (YLE). METHODS In this systematic review, we searched ten online databases from inception to April 13, 2016, without language or temporal restrictions, for cohort, cross-sectional, and experimental studies that compared exposure to carbon monoxide, black carbon, nitrogen dioxide, and fine and coarse particles in active commuters (pedestrian or cyclist) and commuters using motorised transport (car, motorcycle, bus, or massive motorised transport [MMT-ie, train, subway, or metro]). We excluded studies that measured air pollution exposure exclusively with biomarkers or on the basis of simulated data, reviews, comments, consensuses, editorials, guidelines, in-vitro studies, meta-analyses, ecological studies, and protocols. We extracted average exposure and commuting time per mode of transport and pollutant to calculate inhaled doses. We calculated exposure and inhaled dose ratios using active commuters as the reference and summarised them with medians and IQRs. We also calculated differences in YLE due to fine particle inhaled dose and physical activity. FINDINGS We identified 4037 studies, of which 39 were included in the systematic review. Overall, car commuters had higher exposure to all pollutants than did active commuters in 30 (71%) of 42 comparisons (median ratio 1·22 [IQR 0·90-1·76]), followed by those who commuted by bus in 57 (52%) of 109 (1·0 [0·79-1·41]), by motorcycle in 16 (50%) of 32 (0·99 [0·86-1·38]), by a car with controlled ventilation settings in 39 (45%) of 86 (0·95 [0·66-1·54]), and by MMT in 21 (38%) of 55 (0·67 [0·49-1·13]). Overall, active commuters had higher inhalation doses than did commuters using motorised transport (median ratio car with controlled ventilation settings 0·16 [0·10-0·28]; car 0·22 [0·15-0·30]; motorcycle 0·38 [0·26-0·78]; MMT 0·49 [0·34-0·81]; bus 0·72 [IQR 0·50-0·99]). Commuters using motorised transport lost up to 1 year in YLE more than did cyclists. INTERPRETATION Proximity to traffic and high air interchange increased the exposure to air pollution of commuters using motorised transport. Larger inhalation rates and commuting time increased inhaled dose among active commuters. Benefits of active commuting from physical activity are larger than the risk from an increased inhaled dose of fine particles. FUNDING Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS), National Health and Medical Research Council, Nestlé Nutrition (Nestec), Metagenics, and AXA.

Interventions to Reduce Compulsory Psychiatric Admissions: A Systematic Review and Meta-analysis.

IMPORTANCE Compulsory admissions, defined as admissions against the will of the patient (according to local judicial procedures), have a strong effect on psychiatric patients. In several Western countries, the rate of such admissions is tending to rise. Its reduction is urgently needed. OBJECTIVE To establish which interventions effectively reduce compulsory admissions in adult psychiatric patients in outpatient settings. DATA SOURCES A systematic computerized literature search was performed using EMBASE, MEDLINE, Web of Science, PsycINFO, CINAHL, PubMed (not yet indexed for MEDLINE), Cochrane Central, and Google Scholar. Every database was searched from its inception until April 30, 2015. STUDY SELECTION Randomized clinical trials (RCTs) that studied any kind of intervention designed to reduce compulsory admission rates in adult psychiatric patients (age range, 18-65 years) in outpatient settings were eligible. Eligibility was independently assessed by 2 of us. DATA EXTRACTION AND SYNTHESIS Two of us independently extracted relevant data. The Cochrane Collaborations tool was used for assessing risk of bias. Overall risk reduction (random-effects estimate) was calculated in the following 4 subgroups of interventions: advance statements, community treatment orders, compliance enhancement, and integrated treatment. MAIN OUTCOMES AND MEASURES Relative risk (RR) was calculated on the basis of the number of patients who had been compulsorily admitted. RESULTS Our meta-analyses included 13 RCTs comprising 2970 psychiatric patients. The meta-analysis of the RCTs on advance statements showed a significant 23% (RR, 0.77; 95% CI, 0.60-0.98; I2 = 2.2%) (n = 1102) risk reduction in compulsory admissions. In contrast, the RCTs on community treatment orders (RR, 0.95; 95% CI, 0.81-1.10; I2 = 0.0%) (n = 742), compliance enhancement (RR, 0.52; 95% CI, 0.11-2.37; I2 = 55.7%) (n = 250), and integrated treatment (RR, 0.71; 95% CI, 0.49-1.02; I2 = 49.0%) (n = 876) showed no significant risk reduction in compulsory admissions. CONCLUSIONS AND RELEVANCE The meta-analysis of the RCTs on advance statements showed a statistically significant and clinically relevant 23% reduction in compulsory admissions in adult psychiatric patients, whereas the meta-analyses of the RCTs on community treatment orders, compliance enhancement, and integrated treatment showed no evidence of such a reduction. To date, only 13 RCTs have used compulsory admissions as their primary or secondary outcome measure. This demonstrates the need for more research in this field.

The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review

Importance Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Objective To systematically review studies investigating epigenetic marks in AD or PD. Methods Eleven bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar) were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form. Results Of 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes). There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of α-synuclein gene (SNCA) was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD. Conclusion Many studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND.